SF424 (R&R) Tocagen Inc. Phase 2/3 Study of Toca 511 and Toca FC vs SOC in Recurrent GBM/AA Research & Related Other Project Information 7. Project Summary/Abstract High grade gliomas (HGG) that includes glioblastoma (GBM; Grade 4 glioma) and anaplastic astrocytoma (AA; Grade 3 glioma) are the most common and aggressive form of malignant brain tumors in adults, accounting for about 60% of all primary brain cancers (Ostrom 2015). Prognosis for patients with HGG is poor and recurrence is common. Despite improvements in treatment, the average lifespan for patients diagnosed with recurrent HGG is only 6-9 months. With limited treatment options and low survival rates, there remains a significant unmet medical need and new approaches are needed against this devastating disease. Tocagen is developing Toca 511 in combination with Toca FC for the treatment of recurrent HGG. Toca 511 is an investigational retroviral replicating vector (RRV) that encodes a prodrug activator enzyme, cytosine deaminase (CD). When used in combination with Toca FC, an investigational extended-release formulation of 5-fluorocytosine (5-FC; also known as flucytosine), the orally administered 5-FC is converted by the CD enzyme to the anticancer drug 5-fluorouracil (5-FU), directly in cancer cells infected with Toca 511. Toca 511 is designed to selectively infect cancer cells, as it infects only actively dividing cells and replication is further restricted by innate and adaptive immune responses that are defective in malignant cells but intact in normal tissues (Ostertag 2012). Preclinical and limited clinical data support a dual mechanism of action for this immunotherapeutic combination, by direct tumor cell killing through local generation of 5-FU, and immune activation of T lymphocytes and cytotoxic T lymphocytes against the cancer cells. This approach is also designed to avoid the toxicities seen with systemically administered 5-FU, as well as the autoimmune toxicities commonly experienced with other immunotherapies. Three Phase 1 clinical studies of Toca 511 and Toca FC in recurrent HGG are ongoing to evaluate the safety and efficacy of different modes of administration of Toca 511 (intratumoral injection, injection of the cavity wall following tumor resection, and intravenous). Across these studies, the combination therapy has been evaluated in more than 100 subjects and has been well tolerated. Preliminary efficacy analyses indicate a substantially prolonged median survival, with an approximate 6-month improvement relative to clinical trials of drugs used as standard of care for recurrent HGG. These data warrant further investigation of this therapy, and supported Fast Track designation granted by FDA for Toca 511 and Toca FC in recurrent HGG. Orphan-drug designation has been granted by OOPD for Toca 511 and Toca FC in glioblastoma. This Phase 2/3 study is a randomized, controlled study of Toca 511 and Toca FC versus standard of care in recurrent GBM/AA. The primary endpoint is overall survival and the study will be conducted across approximately 80 clinical sites. The study is designed to show superiority over existing therapy and is intended as a pivotal study to support registration of Toca 511 and Toca FC in recurrent HGG.